Dental composition comprising chelator and base

ABSTRACT

The present invention relates to non-toxic consumable compositions and formulations comprising chelator and base having synergistic effects on microbial metabolism and/or growth and/orpathogenic effectors and their use to promote and maintain health in mammals. The current invention also relates to non-toxic consumable compositions comprising more than one chelator and/or more than one base. The present invention further relates to methods for selecting said chelator and base composition and methods for detecting conditions in which selected compositions may be used. The present invention relates to the synergistic compositions and methods of their use for maintaing health, promoting health and treating diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Pat. Application No. 61/851,748, filed Mar. 12, 2013 and U.S. Provisional Pat. Application No. 61/965.678, filed Feb. 5, 2014, the disclosures of each of which are incorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION

Microbes play a central role in both mammalian health and disease, with certain microbes playing a central role in host physiology and health while other microbes promote or exacerbate disease. Health-promoting and pathogenic microbes may include bacteria, fungi, parasites and other microbes and may be found in biofilms.

Microbial biofilms are aggregates of microbial cells that adhere to each other and to a surface. The adherent cells are frequently embedded within a self-produced matrix, also referred to as an extracellular matrix generally composed of extracellular nucleic acids, proteins and polysaccharides (commonly dextran). Biofilms have been demonstrated to exist on biological or inanimate surfaces in home, agricultural, industrial and healthcare settings. A problem is often encountered with biofilms harboring, pathogenic microbes and their toxic effectors that pose a health risk.

It is recognized that antibiotics have multiple limitations in their ability to inhibit the pathogenic effects of biofilms in home, agricultural, industrial and healthcare settings. Numerous attempts to neutralize the pathogenic effects of biofilms including behavioral changes, procedural changes, anti-microbial coatings and next generation antibiotics, have been made with limited success and pose significant toxicity risk to mammals. Non-toxic and effective compositions and methods of use are needed to limit the adverse effects of microbes and microbial biofilms with limited disruption of the healthy microbial flora.

Throughout this specification, various patents, patent applications and other types of publications (e.g., journal articles) are referenced. The disclosure of all patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety for all purposes.

BRIEF SUMMARY OF THE INVENTION

The invention provided herein discloses, inter alia, non-toxic compositions comprising a synergistic amount of chelator and base for limiting the adverse effects of microbes and microbial biofilms while at the same time, limiting disruption of healthy microbial flora in an individual.

Accordingly, in one aspect, provided herein are compositions comprising a chelator and a base, wherein the chelator and base provide microbial affecting activity. In some embodiments, the chelator is selected from the group consisting of siderophores, natural chelators and synthetic chelators. In another embodiment, the chelator is cyclodextrin or cyclodextrin derivative, ferrichrome, citrate, EDTA, EGTA, pectin or modified pectin. In another embodiment, more than one chelator is used. In another embodiment, the concentration of chelator is between 0.0005% and 30% of the composition. In another embodiment, the base is selected from the group consisting of natural bases, synthetic bases and agents having basic properties. In another embodiment, the base is KOH, NaOH, pyridoxal-5-phosphate, pyridoxamine, pyridoxine, vitamin K, lysine, arginine, lysozyme, alpha-galactase, tris amine or sodium bicarbonate. In another embodiment, more than one base is used. In another embodiment, the concentration of base is between 0.0001% and 15% of the composition. In another embodiment, the composition further comprises an enhancer. In another embodiment, the enhancer comprises proline, phenylalanine, boric acid, ascorbic acid or extracts from citrus, berries, teas, peppermint, mint or cinnamon. In another embodiment, the concentration of the enhancer is between 0.0001% and 10% of the composition. In another embodiment, the composition is for oral care. In another embodiment, the base comprises sodium bicarbonate and pyridoxal-5-phosphate and the chelator comprises alpha-cyclodextrin. In another embodiment, the composition is formulated in a tablet, capsule, rapid melt tablet, thin strip, gum or mouthwash. In another embodiment, the composition administered at least once per day. In another embodiment, the composition is used to promote oral health, treat or prevent cavities, periodontitis, halitosis and gingivitis. In another embodiment, the composition is used following consumption of a phosphoric acid or ascorbic acid-containing beverage. In another embodiment, the composition is used following consumption of food.

In another aspect, provided herein are methods of promoting oral health in an individual comprising: (i) identifying an individual at increased risk for developing or exhibiting signs of oral disease, (ii) measuring pH, leukocyte esterase, nitrate, microbial marker levels, or plaque-staining dye retention in the mouth of the individual, (iii) comparing said levels to healthy levels to determine if oral pathology is present, and (iv) if evidence of oral pathology is present, contacting an effective amount of a composition comprising a chelator and a base to the oral surface. In some embodiments, said method is repeated on a daily, a monthly, quarterly or annual basis. In some embodiments, said composition comprises EDTA or alpha-cyclodextrin and sodium bicarbonate or pyridoxal-5-phosphate. In some embodiments, the effective amount of EDTA and alpha-cyclodextrin is between 0.0001% and 30% of the composition. In some embodiments, the effective amount of sodium bicarbonate and pyridoxal-5-phosphate is between 0.0001% and 15% of the composition. In some embodiments, oral pathology is indicated by the individual having an oral pH below 6.2. ln some embodiments, the individual is determined to have oral pathology based on the presence of one or more of the following: halitosis, tooth plaque, tooth decay, or a cavity. In some embodiments, the individual is determined to have oral pathology based on the presence of Streptococcus mutans.

In further aspects, provided herein are methods for limiting or eliminating microbes and/or microbial biofilms in an oral cavity of an individual comprising contacting a surface in the oral cavity with an effective amount of a composition comprising a chelator and a base. In some embodiments, said method is repeated on a daily, a monthly, quarterly or annual basis. In some embodiments, said composition comprises EDTA or alpha-cyclodextrin and sodium bicarbonate or pyridoxal-5-phosphate. In some embodiments, the effective amount of EDTA and alpha-cyclodextrin is between 0.0001% and 30% of the composition. In some embodiments, the effective amount of sodium bicarbonate and pyridoxal-5-phosphate is between 0.0001% and 15% of the composition. In some embodiments, the method further comprises assessing oral pathology in the individual, wherein oral pathology is indicated by the individual having an oral pH below 6.2. In some embodiments, the method further comprises assessing the individual for oral pathology based on the presence of one or more of: halitosis, tooth plaque, tooth decay, and/or a cavity. In some embodiments, the method further comprises assessing the individual for the presence of Streptococcus mutans.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B depict the effect of agents with increasing base properties +/- chelator on microbial growth.

FIG. 2 depicts the effect of individual agents vs. synergistic effect of agent combinations on biofilms.

FIG. 3 depicts the effect of individual agents vs, agent combinations on microbial acid production.

FIGS. 4A and 4B depict the effect of compositions and formulations on human oral health markers.

FIGS. 5A and 5B depict an exemplary differential effect on pathogenic and commensal microbes.

FIG. 6 depicts an exemplary effect of chelator and basicity of agents on microbial growth.

FIG. 7 depicts an exemplary effect of chelator and base compositions on fungal growth.

FIGS. 8A, 8B, and 8C depict an exemplary effect of chelator and base compositions on food biofilms.

DETAILED DESCRIPTION

The present invention generally relates to non-toxic compositions comprising a synergistic amount of chelator and base, whereby said base may comprise one or more hydroxyl group, pyridine ring, nitrogen group or amine group and whereby said chelator may comprise one or more ringed structure capable of chelating metal, lipid, volatile aromatic compound or microbial component. Said compositions may comprise a chelator, a base and an enhancer, whereby said enhancer enhances the utility of the chelator or base. Said compositions may be used to limit microbial growth and unwanted metabolic activity of microbes by contacting a surface to formulations comprising synergistic chelator and base compositions. Said compositions may be used to selectively inhibit the growth and viability of certain microbes while maintaining the viability of many commensal microbes of the flora, Said compositions may be used to selectively alter the metabolism of certain microbes. Said compositions may be used to prevent or treat conditions where microbes induce host inflammation. Said compositions may comprise consumable formulations or may comprise topical formulations. In certain aspects, said compositions may be administered to biological and inanimate surfaces comprising a microbial biofilm. Non-toxic compositions of the current invention may be applied frequently to a biological or inanimate surface to promote oral care, skin care, food safety, overall health and surface care. Non-toxic compositions may be used in products for oral care, skin care, food safety, overall health and surface care.

I. Definitions

As used herein, the singular form “a”, “an”, and “the” includes plural references unless indicated otherwise.

It is understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of” aspects and embodiments.

An “individual” can be a vertebrate, a mammal, or a human. Mammals include, but are not limited to, farm animals, sport animals, pets, primates, mice and rats. Individuals also include companion animals including, but not limited to, dogs and cats. In one aspect, an individual is a human.

An “effective amount” or “therapeutically effective amount” refers to an amount of therapeutic compound, such as a composition comprising a chelator and a base, administered to an individual, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

A “clinician” or “medical researcher” or “veterinarian” as used herein, can include, without limitation, doctors, nurses, physician assistants, lab technicians, research scientists, clerical workers employed by the same, or any person involved in determining, diagnosing, aiding in the diagnosis or influencing the course of treatment for the individual.

It is intended that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that fails within such broader numerical range, as if such narrower numerical ranges were all expressly written herein,

II. Compositions of the Invention

Disclosed herein are non-toxic compositions, comprising chelator and base, for use in limiting microbial growth and unwanted metabolic activity and pathogenic effectors of microbes on surfaces. Said compositions may be applied to a biological or inanimate surface. Surfaces may comprise biological surfaces such as food, dermal surfaces, tooth surfaces, mucosal surfaces, gut surfaces, ocular surfaces or other and may comprise inanimate surfaces such as objects, floors, counters, utensils, handles, or other.

Also disclosed herein are non-toxic consumable compositions, comprising chelator and base, for use in limiting microbial growth, biofilm production and unwanted metabolic activity and pathogenic effectors of microbes involved in mammalian disease. Many diseases have an underlying microbial or microbial-induced inflammatory component that contributes to disease initiation or progression. Both gram-positive and gram-negative bacteria contain several components within their membranes, such as lipopolysaccharide (endotoxin), lipoteichoic acid, CpG DNA. flagella, pili, and other antigenic molecules that are potent agonists of Toll-like receptors (TLRs), which induces pro-inflammatory cytokine secretion ofepithelial cells and immune cells including IL-1,IL-6, and TNF-α. Similarly, fungi and viruses may also contain antigenic molecules and TLR agonists that may trigger inflammation in a local or systemic manner, depending on the identity of the microbe, its pathogenic potential, and extent of overgrowth or metabolic activity or in cases of acute a chronic infection or intoxification.

The compositions disclosed herein may comprise one or more chelator and one or more base. Said compositions may also comprise one or more chelator and one or more base and one or more enhancer.

A. Chelators

Chelators may comprise heterogeneous synthetic or naturally-occurring molecules capable of coordinating, and in some cases, binding cargo. Examples of cargo comprise, without limitation, metals, lipids, volatile aromatic compounds, carbohydrates, microbial components and microbes. Chelators may have more than one donor atom that may coordinate a single cargo. Chelators may also be able to coordinate more than one cargo and is dependent on chelator size and coordination groups. Chelators may be classified according to the number of donor atoms correctly positioned for potential binding to a Lewis acid or other cargo. Chelators may be bidentate, tridentate and polydentate in nature (for example, EDTA is hexadentate). Additionally, chelators may by macrocyclic whereby a large ring compound may contain several donor atoms that may bind a Lewis acid inside said ring structure. A chelator:cargo complex is called a chelate.

Examples of suitable chelators that may be used in said composition include, but are not limited to, cyclodextrins, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, δ-cyclodextrin, methyl-β-cyclodextrin, ethylenediamine, diethylenetriamine, EDTA, EGTA, thiocyanate, porphine, heme, nitrilotriacetic acid, rhodotonilic acid, citrate, anachelins, ferrioxamines, deferoxamine mesylate, cellulose, methylcellulose, carboxymethylcellulose, citrus pectins, apple pectins, orange pectins, carrot pectins, amidated pectins, amidated low methoxyl pectin, high-ester pectins, low-ester pectins, microbial cellulosic material, agar, lignin, curcumin, chlorophylls, resveratrol, alginate, tannins, quercetin, oleuropein, HEDTA, DTPA, EDDHA, succimer, dimercaprol and derivatives thereof. Examples of chelator derivatives include but are not limited to tosylated, acylated, hydroxylalkylated, alkylated, carboxylated. methylated, hydroxypropylated, hydroxylated, sulfoalkylated, amidated, phosphorylated and sulfonated forms and the like. Said chelators may be used in free or salt form. Non-limiting examples of chelators and their use are provided in Table 1.

Suitable chelators may be used in liquid, gel, paste, creme and ointment formulations at concentrations ranging from about 500 mM to about 0.1 nM per dose, depending on the use. Some compositions may comprise chelator from about 500 mM to about 1 mM per dose. Some compositions may comprise chelator from about 500 µM to about 1 µM per dose. Other compositions may comprise chelator from about 10 µM to about 10 nM per dose. Yet other compositions may comprise chelator from about 800 nM to about 0.1 nM per dose,

Suitable chelators may be used in solid and powder formulations at amounts ranging from about 1,000 mg to about 50 ng per dose, depending on the use. Some compositions may comprise chelator front about 1,000 mg to about 50 mg per dose. Some compositions may comprise chelator from about 1 mg to about 25 µg per dose. Some compositions may comprise chelator from about 10 µg to about 100 ng per dose. Other compositions may comprise chelator from about 1 µg to about 50 ng per dose.

B. Bases

Bases may comprise an agent that donates electrons or hydroxide ions, accepts protons, may behave as Arrhenius bases, Bronsted-Lowry bases and Lewis bases. Arrhenius bases increase the hydroxyl ion concentration in a solution. Bronsted-Lowry bases accept protons. Lewis bases donate electron pairs. Bases may comprise primary, secondary, tertiary or cyclic amines.

Examples of suitable bases that may be used in said composition include, but are not limited to, pyridoxine, pyridoxal-5-phosphate, pyridoxine HCl, vitamin B6, vitamin B12, vitamin K, arginine, polyarginines, lysine, polylysines, uracil, sodium bicarbonate, analine, biogenic amines, methylamine, dimethylamine, trimethylamine, ammonia, propylamines, nitroatialines, haloamines, oximes, sodium hydroxide, potassium hydroxide and derivatives thereof. Said bases may have one or more hydroxyl group, pyridine, pyridine nitrogen group, amine or other and may comprise: vitamin base, nucleotide base, basic amino acid, basic sugar, basic lipid, basic mineral, basic salt, basic small molecule, basic peptide or basic enzyme. Said base may be used in free or salt form. Non-limiting examples of bases and their use are provided in Table 2.

Suitable bases may be used in liquid, gel, paste, creme and ointment formulations at concentrations ranging from about 250 mM to about 750 pM per dose, depending on the potency and use. Some compositions may comprise base from about 250 mM to about 1 mM per dose. Some compositions may comprise base from about 800 µM to about 5 µM per dose. Other compositions may comprise base from about 10 µM to about 100 nM per dose. Yet other compositions may comprise base from about 120 nM to about 750 pM per dose.

Suitable bases may be used in solid and powder formulations at amounts ranging from about 1,000 mg to about 50 ng per dose, depending on the potency and use. Some compositions may comprise base from about 1.000 mg to about 50 mg per dose. Some compositions may comprise base from about 75 mg to about 5 mg per dose. Some compositions may comprise base from about 5 mg to about 100 µg per dose. Other compositions may comprise base from about 150 µg to about 8 µg per dose. Yet other compositions may comprise base from about 7.5 µg to about 50 ng per dose,

C. Enhancers

An enhancer may comprise a synthetic or natural agent that enhances the effects of chelator or base in said composition. Enhancers may act by activating said chelator or said base: may protect or preserve said chelator or said base; may promote synergism between said chelator and said base; may act in a supplemental manner to promote synergistic effects between chelator and base to reduce the total dose of each active agent used: or other.

Examples of suitable enhancers that may be used in said composition include, but are not limited to, antacids, ion channel antagonists, proton transporter antagonists, bacteriocins, sugar hydrolyzing enzymes, neutral sugars, sugar alcohols, xylitol, mannitol, sorbitol. Stevia, antimicrobial lipids, iron-binding proteins, plant extracts and derivatives thereof. Other non limiting examples of suitable enhancers may include extracts and oils of green tea, mint, peppermint, cinnamon, spearmint, clove, aloe, ginger, lemongrass, avocado, olive, pomegranate, acai, and citrus. Other examples of suitable enhancers may include, without limitation, binding compounds such as polyethylene glycol, polyvinyl pyrrolidone, magnesium stearate and others. Yet other examples of suitable enhancers may be, without limitation, ascorbic acid, phenylalanine, histatins, statherins, proline-rich proteins, lipase, sialoperoxidase, adhesion-modulating proteins, carbonic anhydrases, amylases, peroxidases, lactoterrin, and mucins. Said enhancers do not inhibit that activity of chelator or base in said composition.

Suitable enhancers may be used in liquid, gel, paste, crème and ointment formulations at concentrations ranging from about 100 mM to about 50 pM per dose, depending on the potency and use. In some embodiments, suitable enhancer concentrations may range from about 100 mM to about 5 mM per dose. In some embodiments, suitable enhancer concentrations may range from about 5 mM to about 50 µM per dose. In some embodiments, suitable enhancer concentrations may range from about 75 µM to about 500 nM per dose. In other embodiments, suitable enhancer concentrations may range from about 1 µM to about 10 nM per dose. Yet in other embodiments, suitable enhancer concentrations may range from about 25 nM to about 50 pM.

Suitable enhancers may be used in solid and powder formulations at amounts ranging from about 5,000 mg to about 10 ng per dose, depending on the potency and use. In some embodiments, suitable enhancer amounts may range from about 5,000 mg to about 150 mg per dose. In some embodiments, suitable enhancer amounts may range from about 200 mg to about 5 mg per dose. In some embodiments, suitable enhancer amounts may range from about 5 mg to about 150 µg per dose. In other embodiments, suitable enhancer amounts may range from about 500 µg to about 10 µg per dose. Yet in other embodiments, suitable enhancer amounts may range from about 25 µg to about 500 ng. Yet in other embodiments, suitable enhancer amounts may range from about 750 ng to about 10 ng per dose.

Chelators, bases and enhancers, or their acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as, their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as reverse phase HPLC. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

Chelators, bases and enhancers or salts thereof may form a solvate and/or a crystal polymorph, and the present invention contains such solvates and crystal polymorphs of various types. A solvate means a solvate of the compound of the present invention or its salt, and example includes solvate of which solvent is alcohol (e.g., ethanol), hydrate, or the like. Example of hydrate includes monohydrate, dihydrate or the like, A solvate may be coordinated with an arbitrary number of solvent molecules (e.g., water molecules). The compounds or salts thereof may be left in the atmosphere to absorb moisture, and a case where adsorbed water is attached or a case where hydrate is formed may arise. Moreover, the compounds or salts thereof may be recrystallized to form their crystal polymorph.

D. Pharmaceutical Compositions

Any of the chelator and base compositions disclosed herein may be formulated into a pharmaceutical and may comprise combinations of chelator and base as the active ingredients. Pharmaceutical compositions may also comprise enhancers.

In some compositions comprising a pharmaceutically acceptable dose of chelator or base or comprising a pharmaceutically acceptable chelator or base may require FDA approval as a pharmaceutical for use to treat a microbe-mediated inflammatory disease.

Pharmaceutical compositions may be formulated with appropriate pharmaceutically acceptable excipients, carriers, diluents or vehicles, and may be formulated into preparations in solid, semi-solid, liquid, gels, pastes, suspension, emulsion, or gaseous forms, and may be formulated into a pharmaceutically acceptable dosage form such as: tablets, capsules, caplets, gums, powders, granules, ointments, crèmes, solutions, suspensions, emulsions, suppositories, injections, inhalants, gels, nanoparticles, microspheres, and aerosols. As such, administration may be achieved in various ways, usually by oral or topical administration. In pharmaceutical dosage forms, the chelator and base may be administered in the free form or in the form of their pharmaceutically acceptable salts, or they may also be used in a time-release formulation, or they may be administered sequentially in a discrete manner, or they may also be used in combination with other pharmaceutically active compounds.

The term “pharmaceutical dose” or “pharmaceutical dosage form,” refers to physically discrete units suitable as unitary dosages for humans and other mammals, each unit comprising a predetermined quantity of agents in an amount calculated sufficient to produce the desired effect in association with an acceptable diluent, carrier, or vehicle of a formulation. The specifications for the unit dosage forms may depend on the particular chelator and base combination employed, the effect to be achieved, the route of administration and the pharmacodynamics associated with the mammal.

For demonstrating the synergistic activity of the selected chelator and base agents to be used in a pharmaceutical composition and for establishing an appropriate fixed-dose ratio for efficacy against microbe-mediated or microbe-enhanced inflammatory diseases, varying amounts of the two agents are administered to appropriate animal models of inflammatory disease, either at a time of active disease (following disease onset) or at an early time point representative of pre-clinical disease, and the effect on disease activity or progression is measured. Alternatively, the effects of varying amounts of the two agents may be tested on a cellular response mediating inflammation that may be involved in the pathogenesis of said disease. Alternatively, the effects of varying amounts of the two agents in various formulations may be tested on a microbial response; the presence, absence or degree of pathogenic effectors; metabolic processes and/or growth that may be involved in the pathogenesis of said disease as a means to determine the appropriate dose and ratio for use as a pharmaceutical composition.

In some pharmaceutical compositions, suitable chelators may comprise cyclodextrins, pectins, modified pectins, ethylenediamine, diethylenetriamine, EDTA, EGTA, thiocyanate, porphine, heme, nitrilotriacetic acid, rhodotorulic acid, citrate, anachelins, ferrioxamines, deferoxamine mesylate, their salts, derivatives or other.

In some pharmaceutical compositions, suitable bases may comprise analines, biogenic amines, methylamine, dimethylamine, trimethylamine, pyridoxine, pyridoxal-5-phosphate, pyridoxamine, ammonia, sodium bicarbonate, ammonium salts, propylamines, nitroanalines, haloamines, oximes, sodium hydroxide, potassium hydroxide or other. For oral formulations, the agents may be used alone or in combination with appropriate additives to make tablets, powders, granules, gums, lozenges, rapid melt tablets, capsules, gels, pastes, solutions or suspensions. Said formulations may further comprise conventional additives, such as xylitol, mannitol, sorbitol, stevia or the like; with binders, such as crystalline cellulose, cellulose derivatives, acacia, starches, gelatins or the like; with disintegrators, such as starches, carboxymethylcellulose or the like; with lubricants, such as talc, magnesium stearate or the like; and if desired, with diluents, buffering agents, moistening agents, preservatives, and flavoring agents.

Acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are commercially available. Moreover, acceptable auxiliary substances, such as pH-adjusting and buffering agents, tonicity-adjusting agents, stabilizers, wetting agents and the like are commercially available. Any compound useful in the methods and compositions of the invention can be provided as an acceptable base-addition salt. “Acceptable base-addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the fluoride, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, fluoride, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, methylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and the like,

E. Nutritional Supplement Compositions

Any of the chelator and base compositions disclosed herein may be Generally Recognized as Safe. (GRAS) and may be used in amounts at or below the FDA recommended daily allowance. Said compositions may be used as a nutritional supplement to promote health. In some embodiments, compositions may be used to promote health in a localized manner and may be dependent on the route of administration, dose or absorption kinetics and dynamics.

Said compositions may be formulated with acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, pressed powder, powder, liquid, gel, suspension, emulsion, or gaseous forms, and may be formulated into preparations such as liquids, syrups, concentrates, tablets, capsules, caplets, powders, rapid melts, thin strips, granules, ointments, crèmes, solutions, suspensions, emulsions, suppositories, injections, inhalants, gels, microspheres, nanoparticles, crystals and aerosols. As such, dose administration may be achieved in various ways, usually by oral administration. In nutritional supplement dosage forms, the chelator and base may be administered in the form of their acceptable salts, or they may also be used in a time-release formulation, or they may be used in combination with other nutritional supplement compounds.

Nutritional supplement compositions may comprise suitable chelators such as: cyclodextrins such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, δ-cyclodextrin, methyl-β-cyclodextrin, and their derivatives; celluloses such as methylcellulose, carboxymethylcellulose, cellulosic material from algae and lignin and their derivatives; pectins from citrus, apple, orange, carrot or other; modified pectins such as amidated pectins, amidated low methoxyl pectins, high -ester pectins, low-ester pectins and other; and various other chelators such as agar, curcumin. chlorophylls, resveratrol, alginate, tannins, quercetin, oleuropein, EDTA and EGTA.

Nutritional supplement compositions may comprise suitable bases such as: vitamin bases such as pyridoxine, pyridoxamine, pyrodoxal-5-phosphate, pyridoxine HCl, vitamin B6, vitamin B12. vitamin K; basic amino acids and derivatives such as arginine, polyarginines, lysine, polylysines, protamine sulfate; uracil; basic salts such as sodium bicarbonate and other: sodium hydroxide and potassium hydroxide.

For oral formulations, the agents may be used alone or in combination with appropriate additives to make tablets, powders, pressed powders, crystals, granules, capsules, gums, lozenges, rapid melt tablets, capsules, gels, thin strips, pastes, solutions or suspensions. Said formulations may further comprise conventional additives, such as xylitol, mannitol, sorbitol, stevia or the like; with binders, such as crystalline cellulose, cellulose derivatives, acacia, starches, gelatins or the like; with disintegrators, such as starches, carboxymethylcellulose or the like; with lubricants, such as talc, magnesium stearate or the like; and if desired, with diluents, buffering agents, moistening agents, preservatives, and flavoring agents.

The agents may be encapsulated in gelatin capsules together with inactive ingredients and powdered carriers, such as, but not limited to, glucose, lactose, sucrose, sucralose, mannose, mannitol, xylitol, stevia, aspartame, neotame, acesulfame potassium, starch, cellulose or cellulose, derivatives, magnesium stearate, stearic acid, sodium saccharin, talcum, magnesium carbonate. Examples of additional inactive ingredients that may be added to provide desirable color, taste, stability, buffering capacity, dispersion or other known desirable features include, without limitation, red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, and edible white ink. Similar diluents may be used to make compressed tablets. Both tablets and capsules may be manufactured as sustained release products to provide for continuous release of agents over a period of minutes. Compressed tablets may be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration may contain coloring and flavoring to increase aesthetic experience

Compressed tablets may be generated using a process known as wet granulation, whereby the active agents may be mixed in powder form with inactive ingredients. Once mixed, the powder may be forced through a mesh screen in a process called dry screening. The mixture may then molded into a tablet using mechanical compression by a punch and die system. The final tablet may then be coated for aesthetics. Compressed tablets may also be generated using a process using a tablet press, whereby the active agents may be mixed in dry powder form with inactive ingredients. Once mixed, the dry powder may be molded into a tablet using mechanical compression by a punch and die system.

For oral administration of dietary supplement compositions to the mucosal surfaces of the mouth, throat and upper digestive tract, the active agents with other suitable agents may be made into formulations such as liquids, fast melting capsules, fast-dissolving tablets, powders, gels, thin strips and lozenges. In one embodiment, a composition may be formulated into a fast-dissolving thin strip and may comprise dehydrated polymer to act as an excipient, such as cellulose, gelatin or starch that, when hydrated under the tongue with saliva may dissolve to release the chelator and base. In another embodiment, a composition may be formulated into a fast-dissolving lozenge and may comprise liquid paraffin, sugar-substitutes, sugar alcohols, non-crystallizing sorbitol solution, flavoring agent, coloring agent or the like, and may release the chelator and base to the tongue, throat and esophagus. In another embodiment, a composition may be formulated into a fast-dissolving tablet and may comprise disintegrant, filler, sugar alcohol, flavoring agent, coloring agent or the like, and may release the chelator and base to the tongue, teeth, gums and mucosal surfaces of the mouth. In another embodiment, a composition may be formulated into a gel and may comprise cellulose, gelatin, pectin or other polymer, sugar alcohols, flavoring agent, coloring agent or the like and may release the chelator and base to the surfaces of the mouth, teeth, tongue, throat, and esophagus.

Acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are commercially available. Moreover, acceptable auxiliary substances, such as pH-adjusting and buffering agents, tonicity-adjusting agents, stabilizers, wetting agents and the like are commercially available. Any compound useful in the methods and compositions of the invention can be provided as an acceptable base-addition salt. “Acceptable base-addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the fluoride, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, fluoride, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylammoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

F. Food Safety, Cosmetic, and Surface-Cleaning Compositions

Any of the chelator and base compositions disclosed herein may be GRAS agents and may be used as food additives to promote health. Food additive compositions may be formulated may be formulated as food sprays, food washes or concentrates. Food safety formulations may be used to promote health or to limit undesired microbial metabolism and thus may serve as food safety agents, food preparatory agents and/or food preservatives.

Some food safety compositions may be used directly on food surfaces or may be used as preservative in food products. Said compositions may comprise EDTA, sodium pyrophosphate and gamma-cyclodextrin as chelator; and pyridoxal-5-phosphate, NaOH, lysine and sodium pyrophosphate as base. Compositions may comprise chelator concentration at about 0.1 mM to about 0.1 µM and base concentration at about 0.1 mM to about 0.1 µM.

Additionally, food safety formulations may be applied frequently or on an as needed basis to surfaces or objects such as: cutting board, kitchen counter, kitchen sink, food-processing devices such as conveyer belts, knives, forks, hooks, gloves or other and food storage devices such as packaging, containers, boxes or other.

In some embodiments, food safety compositions may comprise EDTA, EGTA, rhodotorulic acid and ferrichrome as chelator; protamine sulfate, tris amine, tris (hydroxymethyl) aminomethane hydrochloride, diethylamine hydrochloride, KOH and NaOH as base; and boric acid, and sodium orthovanadate as enhancer. In some surface care compositions acceptable chelator concentrations may range from about 100 mM to about 1 µM, acceptable base concentrations may range from about 500 µM to about 1 µM and acceptable enhancer concentrations may range from about 50 µM to about 10 µM.

In other food safety compositions for use on food preparation surfaces and food storage surfaces may comprise ferrichrome, EDTA and rhodotorulic acid as chelator; KOH, NaOH and sodium bicarbonate as base and sorbic acid as enhancer. In said compositions, EDTA may be used at concentrations of ranging from about 0.1 M to about 0.1 mM, rhodotorulic acid may be used at concentrations of about 10 µM to about 10 µM, ferrichrome may be used at concentrations of about 5 mM to 5 µM; KOH and NaOH may be used at concentrations of about 0.8 M - 0.5 µM; sodium bicarbonate may be used at about 0.1 M to about 0.1 mM; sorbic acid may be used at concentrations of about 0.5 mM to about 0.5 µM.

Any of the chelator and base compositions disclosed herein may be GRAS agents and may be suitable for formulation in a cosmetic to limit undesired microbial growth, undesired microbial metabolism and thus serve as a preservative and/or a deodorant. Cosmetic compositions may be formulated in an elution patch, wipe, pad, sponge, cloth, strip, gel, paste, solution, emollient, serum, moisturizer, make-up, lotion, shampoo, conditioner, gel, mousse, soap, deodorant, antiperspirant, spray, wash and solution and may be used for topical administration.

In some compositions, acceptable chelator and base may be used for veterinary applications such as in formulations for promoting oral health, wound care or other. Veterinary formulations may include sprays, gels, liquids, syrups, tablets, capsules, lotions, salves, or other.

Any of the chelator and base compositions disclosed herein may be used as surface cleaners, disinfectants, or other. Surface treatments may be formulated as concentrates, solutions, sprays, powders, wipes or other. Surfaces may include: biologic surfaces comprising oral, gut, nasal, ocular, otic, topical, food or other; inanimate surfaces comprising structural surfaces, clothing, gloves, diapers, undergarments, kitchen surfaces, bathroom surfaces, painted surfaces, tiled surfaces, door knobs, handles, computers, remote controls, steering wheels, cell phones, manufacturing machinery, hospital surfaces, devices or other.

G. Health-Promoting Compositions

Associations between chronic oral infections and oral inflammation and rheumatologic disease, autoimmune diseases neurodegenerative diseases, respiratory diseases, cardiovascular diseases and stroke, and low-birth-weight/premature births are being realized (U.S. Surgeon General, WHO). Microbe-mediated and microbe-enhanced inflammatory diseases may include autoimmune diseases including rheumatoid arthritis, Crohn’s disease, psoriasis, psoriatic arthritis, systemic lupus erythematosus, oral lichen planus, Behcet’s disease, Sjogren’s syndrome and other autoimmune diseases; degenerative diseases including osteoarthritis, stroke, cardiovascular disease, atherosclerosis, Alzheimer’s disease, other dementias, macular degeneration, chronic obstructive pulmonary disease, halitosis, irritable bowel disease and other degenerative diseases; chronic infections including human immunodeficiency virus infection, hepatitis C virus infection, cytomegalovirus infection, otitis media, periodontal disease, cavities, sinusitis, rhinitis, pneumonia, rheumatic fever, endocarditis, pericarditis, and other viral, bacterial, fungal, parasite and other infection. Accordingly, any of the chelator and base compositions disclosed herein may be used to promote one or more of oral health, cardiovascular health, mental health, and/or systemic health.

Oral Health. Oral health relates to the balance of beneficial and pathogenic activities in the oral and nasopharyngeal cavities and is critically dependent on the relationship between the microbial flora and mucosal immunity. Diseases such as, but not limited to, cavities (CV), gingivitis (OV), periodontal disease (PD), rheumatic fever (RF), otitis media (OM), sinus infection (SI), chronic rhinosinusitis (CRS), chronic halitosis (HT) and pneumonia (PN) may stem from oral imbalance, oral microbial overgrowth, microbial effectors, undesirable microbial metabolic products and/or inflammation.

Cardiovascular Health. Cardiovascular health relates to the balance of beneficial and pathogenic activities in the caidio-pulmonary- vascular system. Build-up of inflammatory plaques and/or chronic infections of the heart, cardio-pulmonary and/or vasculature may arise from microbial biofilm formation, microbial infection, microbial effectors, undesirable microbial metabolic products and/or inflammation. Non-limiting examples of cardiovascular diseases with microbial and microbial-related inflammation may include: Rheumatic fever (RF), atherosclerosis (AS), stroke (ST), cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD).

Mental Health Mental health relates to the balance between beneficial and pathogenic activities of the brain and central nervous system and may be directly or indirectly impacted by build-up of inflammatory plaques and/or chronic infections of the brain and central nervous system and may arise from microbial biofilm formation, microbial infection, microbial effectors, undesirable microbial metabolic products and/or inflammation. Non-limiting examples of mental health conditions comprise Alzheimer’s disease (AD), dementias (DM), depression, Parkinson’s disease, amyotrophic lateral sclerosis and others.

Systemic Health. Systemic health relates to the balance of beneficial and pathogenic activities of organs, organ systems and tissues of the body and may be directly or indirectly impacted by build-up of microbial overgrowth, inflammatory plaques and/or chronic infections in the body. Non-limiting examples of systemic health conditions comprise Beheet’s Disease (BD), Sjogren’s Syndrome (SS.), lichen planus (LP), systemic lupus erythematosus (SLE), Rheumatoid arthritis (RA), and other autoimmune diseases having disease manifestations involving microbes or microbe-mediated inflammation; degenerative diseases such as irritable bowel disease (IBD), colitis (CO), osteoarthritis (OA), diabetes, metabolic diseases and cancers.

Examples of chelator and base compositions for use in promoting health may comprise one or more chelator, base and enhancer. Compositions may comprise EGTA, EDTA, citrate, cyclodextrins, vitamin B12. pectins and deferoxamine mesylate as chelator: KOH. NaOH. lysine, arginine, sodium bicarbonate, a-galactase, pyridoxal-5-phosphate, pyridoxine, pyridoxamine, vitamin B6, lysozyme and vitamin K as base; and ascorbic acid, proline, uracil, remitidine, famotidine, omeprazole and other acid blockers, plant extracts and zinc chloride as enhancer. Commercially available flavoring agents, coloring agents, fillers, excipients, carriers, and buffers may be formulated into health-promoting compositions.

III. Methods of the Invention A. Methods for Promoting Oral Health

Any of the chelator and base compositions (e.g., pharmaceutical compositions) disclosed herein can be used in methods to promote oral health. Many microbial metabolic products have beneficial effects for mammals (examples are fermented foods and beverages). Many other microbial metabolic products have pathogenic effects on mammals (Ramsey et al. (2011) PLOS Pathogens). In some embodiments, administration of compositions comprising chelator and base can affect microbial metabolism, namely acid production. Non-limiting examples of oral pathologies capable of treatment by the methods disclosed herein employing any of the compositions disclosed herein include cavities (CV), gingivitis (GV), periodontal disease (PD), rheumatic fever (RF), otitis media (OM), sinus infection (SI), chronic rhinosinusitis (CRS), chronic halitosis (HT) or pneumonia (PN).

In some aspects, said method can comprise; (i) identifying an individual at increased risk for developing or exhibiting signs of oral disease (ii) measuring pH. leukocyte esterase, nitrate, microbial marker levels, or plaque-staining dye retention in the mouth of the individual. (iii) comparing said levels to healthy levels to determine if oral pathology is present, and (iv) if evidence of oral pathology is present, contacting an effective amount of a composition comprising a chelator and a base to the oral surface.

In another aspect, any of the chelator and base compositions (e.g., pharmaceutical compositions) disclosed herein may be used in methods for limiting or eliminating microbes and/or microbial biofilms in an oral cavity of an individual comprising contacting a surface in the oral cavity with an effective amount of any of the compositions disclosed herein.

B. Methods for Promoting Cardiovascular Health

Any of the chelator and base compositions (e.g., pharmaceutical compositions) disclosed herein can be used in methods to promote cardiovascular health. Non-limiting examples of cardiovascular pathologies capable of treatment by the methods disclosed herein employing any of the compositions disclosed herein include Rheumatic fever (RF), atherosclerosis (AS), stroke (ST.), cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD). In some aspects, said method can comprise: (i) identifying an individual at increased risk for developing or exhibiting signs of a cardiovascular disease and (ii) administering a clinically effective amount of any of the compositions disclosed herein to the individual. In other aspects, said method comprises administering a clinically effective amount of any of the compositions disclosed herein to an individual diagnosed with or thought to be afflicted with a cardiovascular disease.

C. Methods for Promoting Mental Health

Any of the chelator and base compositions (e.g., pharmaceutical compositions) disclosed herein can be used in methods to promote mental health. Non-limiting examples of mental or neurological pathologies capable of treatment by the methods disclosed herein employing any of the compositions disclosed herein include Alzheimer’s disease (AD), dementias (DM), depression, Parkinson’s disease, and amyotrophic lateral sclerosis. In some aspects, said method can comprise: (i) identifying an individual at increased risk for developing or exhibiting signs of a mental disease and (ii) administering a clinically effective amount of any of the compositions disclosed herein to the individual. In other aspects, said method comprises administering a clinically effective amount of any of the compositions disclosed herein to an individual diagnosed with or thought to be afflicted with a mental or neurological disease.

D. Methods for Promoting Systemic Health

Any of the chelator and base compositions (e.g.. pharmaceutical compositions) disclosed herein can be used in methods to promote systemic health. Non limiting examples of systemic pathologies capable of treatment by the methods disclosed herein employing any of the compositions disclosed herein include Behcet’s Disease (BD). Sjogren’s Syndrome (SS), lichen planus (LP), systemic lupus erythematosus (SLE). Rheumatoid arthritis (RA), and other autoimmune diseases having disease manifestations involving microbes or microbe-mediated inflammation; degenerative diseases such as irritable bowel disease (IBD), colitis (CO), osteoarthritis (OA), diabetes, metabolic diseases and cancers, in some aspects, said method can comprise: (i) identifying an individual at increased risk for developing or exhibititig signs of a systemic disease and (ii) administering a clinically effective amount of any of the compositions disclosed herein to the individual. In other aspects, said method comprises administering a clinically effective amount of any of the compositions disclosed herein to an individual diagnosed with or thought to be afflicted with a systemic disease (such as, but not limited to an autoimmune disease or an inflammatory disease).

E. Administration

Any of the chelator and base compositions (e.g., pharmaceutical compositions) disclosed herein may be administered on a frequent basis to affect microbial growth, microbial metabolism, microbial biofilm integrity, microbial biofilm production, microbial toxin production or microbial acid production. Said compositions may be administered on a frequent basis to affect microbial effectors and thus reduce inflammation. Said compositions may be administered on a frequent basis for the promotion and maintenance of health.

It is within the level of skill of a clinician or medical researcher or veterinarian to determine the preferred route of administration and the corresponding dosage form and amount, as well as the dosing regimen, i.e., the frequency of dosing. In some embodiments, the composition may be delivered in multi-dosing format whereby said composition may be administered several times a week, once a day, twice a day, three times a day, or more to achieve the appropriate therapeutic level. However, this generalization does not take into account such important variables as the specific type of microbial species to be affected, the specific inflammatory disease, the specific therapeutic agent involved and its pharmacokinetic profile, and the specific, individual involved. For other approved products in the marketplace, much of this information is already provided by the results of clinical studies carried out to obtain such approval. In other cases, such information may be obtained in a straightforward manner in accordance with the teachings and guidelines contained in the instant specification taken in light of the knowledge and skill of the artisan. The results that are obtained may also be correlated with data from corresponding evaluations of past and current marketed product(s) utilizing comparable clinical testing methods.

Frequency of administration may be once a month, once a week, once a day, up to 3 times per day, up to 10 times a day, before bed and on an as-needed basis. Frequency of administration may be dependent on the identity and concentration of the base and chelator in said composition; and may be dependent on disease risk assessment, disease severity, test results, or personal preference; and may be dependent on formulation.

Individuals and other mammal at increased risk for development of a microbe-mediated or microbe-enhanced inflammatory disease, with early-stage of disease, or with established disease may be treated with a clinically effective amount of any of the compositions disclosed herein to prevent the development of disease, to prevent the progression of disease, and to prevent the progression of the symptoms or signs of disease. The total of a dose of base may generally range from about 0.00003 to about 5 mg/dose and the total of a multi-day dose may range between about 0.0003 to about 25 mg/day. The total of a dose of chelator may generally range from about 0.0005 to about 10 mg/dose and the total of a multi-day dose may range between about 0.003 to about 10 mg/day. The total dose of enhancer may vary and may generally range from about 0.00001 to 1.5 mg/dose.

In some embodiments, an individual may be administered any of the health-promoting compositions disclosed herein, wherein said compositions can comprise a chelator agent of at least about 0.003 mg, at least about 0.006 mg, at least about 0.01 mg, at least about 0.03 mg, at least about 0.06 mg, at least about 0.1 mg, at least about 0.125 mg, at least about 0.25 mg, at least about 0.5 mg, at least about 0.75 mg, at least about 1.0 mg, at least about 3.0 mg, at least about 5.0 mg, at least about 10.0 mg, at least about 25 mg, at least about 50 mg, not more than about 5.0 g; and base agent in a single dose of at least 0.0003 mg, at least about 0.0006 mg, at least about 0.001 mg, at least about 0.003 mg, at least about 0.006 mg, at least about 0.01 mg, at least about 0.03 mg, at least about 0.06 mg, at least about 0.1 mg, at least about 0.3 mg, at least about 0.6 mg, not more than about 30.0 mg.

In some embodiment, an individual may be administered any of the health-promoting compositions disclosed herein, wherein said compositions can comprise cyclodextrin or a cyclodextrin derivative in a single dose of at least about 0.003 mg, at least about 0.006 mg, at least about 0.01 mg, at least about 0.03 mg, at least about 0.06 mg, at least about 0.1 mg, at least about 0.125 mg, at least about 0.25 mg, at least about 0.5 mg, at least about 0.75 mg, at least about 1.0 mg, at least about 3.0 mg, at least about 5.0 mg, at least about 10.0 mg, at least about 25 mg, at least about 50 mg, not more than about 5.0 g: and vitamin B6, pyridoxal-5-phosphate, pyridoxamine, pyridoxine or another vitamin base in a single dose of at least 0.0003 mg, at least about 0.0006 mg, at least about 0.001 mg, at least about 0.003 mg, at least about 0.006 mg, at least about 0.01 mg, at least about 0.03 mg, at least about 0.06 mg, at least about 0.1 mg, at least about 0.3 mg, at least about 0.6 mg, not more than about 30.0 mg; and sodium bicarbonate or other basic salt in a single dose of at least 0.0003 mg, at least about 0.0006 mg, at least about 0.001 mg, at least about 0.003 mg, at least about 0.01 mg, at least about 0.03 mg, at least about 0.06 mg, at least about 1.0 mg, at least about 5.0 mg, at least about 25 mg, at least about 50 mg, at least about 100 mg, at least about 250 mg, at least about 800 mg, at least about 1000 mg, at least about 2000 mg, not more than about 8.0 g.

Any of the chelator and base compositions (e.g., pharmaceutical compositions) disclosed herein may be administered in a manner to deliver base and chelator agents in combination or in sequence, In some embodiments, health-promoting compositions may be administered in a periodic manner. Administration of compositions may occur at least once daily, weekly or monthly or on an as needed basis. Health-promoting compositions may comprise pharmaceutically acceptable formulations (such as carriers or excipients) or may be nutritional supplement formulations. Health-promoting compositions may be commercialized in individual dose forms or in multi-dosing forms.

Methods of use for food safety formulation comprise of contacting the composition to a surface prior to, periodically during and/or immediately following the preparation of food and food products. Preferred methods involve contacting said surface with said compositions for a minimum of 5 seconds. Preferred methods also involve the periodic rinsing of contacted surfaces to effectively remove the neutralized microbes, biofilms and metabolic products.

F. Methods for Selecting Base and Chelator Compositions

Methods of selecting base and chelator compositions depend on use. Compositions may be determined by ranking base, chelator and enhancer agents, from most desired to least desired, for multiple parameters such as safety, solubility, compatibility, pH, potency, taste, consistency, smell and others. Examples of ranking base and chelator agents for determining selection in a composition for a desired use are presented in Tables 1 and 2.

Non -toxic chelator and base compositions may be ranked according to the desired parameters of potency and approved-for-oral-consumption. A desired parameter such as potency for a candidate chelator or base may be given a score of “1” for most desired and a score of “3” for least desired. In one embodiment, candidate chelators, bases and enhancers may be ranked by FDA approval for oral consumption. Agents with a score of “1” may have approval for the desired indication and a score of “3” may not have approval or may not be approved for the desired indication. The resultant overall score may be tabulated and may be used to facilitate selection. In this example, the lowest overall score represents the best candidates for use in a non-toxic composition.

TABLE 1 CHELATORS THAT MAY BE USED IN COMBINATION WITH BASE AGENTS CHELATOR POTENCY CONSUMABLE ANTICIPATED USE* Resveratrol 2 1 O,T,V,F,S Quercetin 1 1 O,T,V,F,S Curcumin 2 1 O,T,V,F,S Oleuropein 2 1 O,T,V,F,S Inositol hexaphosphate 2 1 O,T,V,F,S EGCG 1 1 O,T,V,F,S Amidated Pectins 1 I O,T,V,F,S Algitiate 1 1 O,T,V,F,S Tannic acid 1 1 O,T,V,F Chitosan 2 2 O,T,V,F,S Exopolysaccharide 1 2 F,S Cellulosic material 1 2 O,T,V,F,S Pectins 1 1 O,T,V,F,S Citrate, Citrate salts 3 1 O,T,V,F,S Anachelins 1 3 S Ferrioxamines 1 2 O,T,V,F,S Rhodotorulic acid 1 2 O,T,V,F,S Microbial cellulose. 1 2 O,T,V,F,S Celluloses 2 1 O,T,V,F,S Deferoxamines 1 1 O,T,V,F,S Deferasiroxantine B 1 1 O,T,V,F,S EDTA 1 1 O,T,V,F,S EGTA 1 2 T,V,F,S Chlorophylls 1 2 O,T,V,F,S DMSA 1 2 T,V,F,S DMPS 1 2 T,V,F,S Vitamin B12 1 1 O,T,V,F,S Cyelodextrins 1 1 O,T,V,F,S ^Score 1-3. 1, most; 2, moderate; 3, least. *O: oral administration, T: topical administration. V: veterinary, F: food safety, S: surfaces.

TABLE 2 BASE AGENTS THAT MAY BE USED IN COMBINATION WITH CHELATORS BASE POTENCY CONSUMABLE ANTICIPATED USE* Pyridoxine 1 1 O, T, V, F, S Pyridoxal-5-phosphate 1 1 O, T, V, F, S Vitamin K 1 1 O, T, V, F, S Lysine 2 1 O, T, V, F, S Arginine 2 1 O, T, V, F, S Uracil 3 1 O, T, V, F, S Lysozyme 1 2 O, T, V, F, S Trisamine 2 3 T, V, F, S Tris (hydroxymethyl) amine 2 3 T, V, F, S Sodium bicarbonate 3 1 O, T, V, F, S Protamine sulfate 2 3 O, T, V, F, S D-mahose 1 1 O,T,V,F,S A-galactase 1 1 O, T, V, F, S Remitidine 1 1 O, T, V, F, S Omeprazole 1 1 O, T, V, F, S Famotidine 1 1 O, T, V, F, S Diethylamine 2 3 F, S Sodium phosphate forms 3 1 O, T, V, F, S Dibasic calcium phosphate 3 1 O, T, V, F, S Vitamin B12 2 1 O, T, V, F, S Sodium hydroxide 1 2 O, T, V, F, S Potassium hydroxide 1 2 O, T, V, F, S Pyridoxamine 1 1 O, T, V, F, S ^ Score 1-3, 1, most: 2, moderate; 3, least. *O: oral administration, T: topical administration, V: veterinary, F. food safety, S: surfaces.

Additionally, methods of selecting base, chelator and enhancers for a composition may be determined experimentally by administering a concentration or concentration range of agents to microbes, contaminated surfaces, animal models and/or mammalian cells to achieve a desired outcome. In some embodiments, compositions may be administered to a commensal microbe such as Lactobacillus acidophilus, a pathogenic microbe such as Streptococcus mutans, and human biofilms and may be assessed for efficacy. In some embodiments, compositions may be administered to a mammal or to mammalian cells and the effect of a composition may be evaluated for efficacy. In some applications, compositions may be selected for having optimal anti-pathogen effects with minimal affect to commensal microbes. In some applications, compositions may be selected for having optimal anti-biofilm efficacy. In some applications, compositions may be selected for having optimal anti-growth efficacy. In other applications, compositions may be selected for having optimal effects on microbial metabolism. Yet in other applications, compositions may be selected for having optimal activity against microbe-mediated inflammation.

Additionally, methods for selecting appropriate chelator and base combinations may be achieved through the use of a test. A test may be conducted to identify and quantify parameters such as: pH; sugar content; protein content; the presence of pathogens and/or pathogenic molecules; the presence and/or level of metabolites such as nitrites, nitrates, sulfates, volatile aromatic compounds; the presence and/or level of inflammatory mediators; and others. Methods may relate to conducting a test to identify an optimal composition for use in a specific indication. Methods may also relate to conducting a test to determine the frequency in which composition may be used for optimal results. Methods may also relate to testing frequency to monitor the efficacy of a selected composition and its efficacy over time. Methods may relate to sampling a patient, mammal, or surface followed by performing one or more test on a sample. Methods also relate to performing one or more test in situ through the administration of a test article to a patient, mammal, or surface.

In some embodiments, any of the methods disclosed herein can comprise use of a pH test strip to measure the pH of a sample. Samples may comprise environmental, surfaces, saliva, crevicular fluid, urine, sweat, tears, sebaceous secretions, blood or other. In one embodiment, a test may be conducted using a pH test strip to measure the pH of a sample to help guide the selection of an optimal base and chelator composition. In one embodiment, a test may be conducted using a pH test strip to measure the pH of a sample to help guide the dose, frequency of administration or other of a composition. In one embodiment, a test may be conducted using a pH test strip to measure the pH of a sample to measure the change in pH following administration of a composition and thus may be used to test the efficacy of a composition.

In some embodiments, any of the methods disclosed herein can comprise use of stains to test for the presence or burden of microbes, microbial biofilm, microbial metabolite, microbial effector or inflammation. In some embodiments, a test may be conducted using a dextran staining dye to measure the presence and abundance of biofilm in a sample or on a surface: may be used to help guide the selection of an optimal base and chelator composition: may be used to assess burden and may be to help guide the dose of composition to be administered; the frequency of administration or may be used to measure the change in biofilm burden following administration of a composition and thus may be used to test the efficacy of a composition.

Other non-limiting examples of tests relate to the use of immunoassays to detect and quantify the amount of a specific analyte in a sample. ln some embodiments, immunoassay tests may be approved for use in the diagnosis of a microbial-related inflammatory disease. Examples of analytes to be measured may comprise: pathogen markers, metabolic markers, microbial effectors, toxins and inflammatory markers such as inflammatory cytokines, chemokines, antigen-specific IgG, IgA, IgM and IgE, and leukocyte esterase and other immune-rotated enzymes. In some embodiments, test results may be used to help guide the selection of an optimal base and chelator composition: may be used to assess disease severity and may be to help guide the dose of composition to be administered; the frequency of administration or may be used to measure the change in disease status following administration of a composition and thus may be used to test the efficacy of a composition.

Yet other non-limiting examples of tests relate to the use of chemical tests to detect and quantify the amount of specific analyte in a sample, In some embodiments, chemical tests may be approved for use in the diagnosis of a microbial-related inflammatory disease. Examples of analytes to be measured comprise glucose, nitrite, nitrate, sulfite, sulfate, aromatic volatile, compounds or other. In some embodiments, test results may be used to help guide the selection of an optimal base and chelator composition; may be used to assess disease severity and may be to help guide the dose of composition to be administered: the frequency of administration or may be used to measure the change in disease status following administration of a composition and thus may be used to test the efficacy of a composition.

EXAMPLES Example 1. Compositions to Affect Microbial Growth

Compositions comprising chelator and base can affect microbial growth. It was discovered that the administration of compositions comprising chelator and base inhibit pathogen growth in a biofilm. Static cultures of pathogen S. mutans, commensal L. acidophilus (purchased from ATCC) or complex biofilms isolated from human dental plaque by sterile swab and were grown for 24-72 h in polystyrene microtiter plates and allowed to form biofilms. Wells were treated briefly with compositions or controls prior to repletion with sterile media (RPMI, pH 7.2) and their effects on pathogen growth was then evaluated using standard microbiological methods for plating and counting colony forming units (CFUs) on TSA plates (FIGS. 1, 5-6 ). Optimal microbial growth-interrupting compositions were identified for each pathogen and for the microbes residing in the donor plaque by screening chelator, base and enhancer agents at various concentrations and combinations.

An amino acid may be used in combination with a chelator to affect microbial growth. The more basic a side chain is (at neutral pH) on an amino acid, the more potential growth affecting potential exists when used in combination with a chelator (FIG. 6 ). A chelator may be, for example, a siderophore such as rhodotorulic acid, rhizoferrin, azotobactin, ferrichrome, desferrioxamine B, bacillibactin, and others. In some embodiments, a chelator may be plant-derived such as pectin, carboxymethylcellulose, cellulose, cyclodextrin and others.

Furthermore, it was discovered that the administration of compositions comprising chelator and base can inhibit the growth of pathogens in established biofilms. Briefly, microbial biofilm was harvested from human mucosal and dermal surfaces and cultured in 96-well flat-bottom polystyrene microtiter plates and spiked with ~ 103 CFU of pathogen. Pathogen-containing biofilms were briefly exposed to saline control or compositions and were then repleated with RPMI media, pH 7.2 Pathogen growth in saline-treated biofilms was compared to pathogen growth in composition-treated biofilms. Pathogens were recovered from treatment samples by serial dilution in sterile saline followed by plating on TSA blood agar plates. Recovered CFUs were tabulated. Exemplary data are presented in FIG. 6 and demonstrate that the application of chelator and base compositions can be effective at limiting the growth of pathogens, even in the presence of a protective biofilm.

Example 2. Compositions to Affect Biofilms

Compositions comprising chelator and base can affect biofilm formation, development, composition and/or integrity. Microbial biofilms are linked to persistent infection, chronic inflammation and chronic diseases. Clearance or containment of microbial biofilms is important and there are limited compounds capable of killing pathogens that reside in biofilms due to poor penetration and/or slow kinetics of antibiotics into biofilms, enabling pathogen survival and disease persistence despite the presence of many antibiotics and antiseptics on the market (Brown et al. (1988) J Antimicrob Chemother. 22:777-780; Lewis K. (2001) Antimicrob Agents Chemother. 45:999-1007).

Microbes were cultured in growth media and plated at 10³ CFU/well in a 96 well microtiter plate and cultured for 24 h. Wells were then treated with 10-50 µL of media only as control or with media + chelator agents, base agents, acid agents, neutral agents or enhancer agents for 30 min at RT followed by repleation in 100 µL of fresh RPMI pH 7.2. Plates were then incubated for an additional 48-72 h prior to harvest. Wells were washed 3x in PBS and residual biofilm was stained using crystal violet. Wells were washed 4x in PBS and the amount of retained stain was measured. It was initially determined that strong base alone may inhibit biofilms, however, strong base is toxic to most organisms and such caustic compounds are not meant for frequent exposure. Unexpectedly, it was observed that biofilms were inhibited by the administration of a chelator at pH of 7.0-8.0 (human physiologic pH), but not below pH 6.8. Furthermore, it was determined that low concentrations of base (0.8-1.6 µM) in the presence of low concentrations of chelator (1 µM) is superior to higher concentrations of base (50 µM) or higher concentrations of chelator (100 µM) alone in blocking biofilms. Synergistic effects were evaluated and numerous compounds were examined for their ability to synergistically act with chelators to inhibit biofilm formation (examples of some test compounds analyzed for synergy with chelators are presented in Table 2), An example of screening results is presented in FIG. 2 . Additional dose titrations studies were performed for select compounds (examples of dose titration are presented in FIG. 3 ). It was discovered that compositions comprising low concentrations of chelator and base, or compositions comprising low concentrations of chelator, base and enhancer, were significantly more effective than higher doses of the individual agents (FIGS. 1-3 ). These data present some examples of chelator and base compositions having biofilm affecting activity. These data also present some examples of chelator and base compositions that may be used to inhibit biofilm formation, development, composition and/or integrity.

Example 3. Compositions to Affect Microbial Metabolism

Compositions comprising chelator and base can affect microbial metabolism. Many microbes undergo metabolic processes that generate acidic waste products, many of which are secreted into the surrounding environment. Sugar fermentation is a metabolic process whereby carbohydrates are convened into lactic acid, acetic acid or other acids. Examples where microbial acid production and its secretion into the surrounding environment have undesired consequences are demineralization of tooth enamel, metabolic disruption of neighboring mammalian cells (acid erosion of the gums, skin flaking on the scalp (also known as dandruff)), immune cell activation, cancer and others.

It was initiallly determined that biofilm production can be disrupted by the administration of a chelator under basic conditions, but not under acidic conditions (FIG. 2 ). Using similar microtiter plate based approach, oral commensals and oral pathogens were cultured in RPMI pH 7.2 and were briefly exposed to single base or chelator agents or combinations of bases and chelators. Assessment of metabolic output 24, 48 and 72 hr post-treatment was measured, pH was determined using the acid-sensitive dye Phenol Red to measure acid production in each well, with secondary testing using a pH test strip (pHion and Seimens). Microbial metabolism was also assessed by Multistix10 SG strips for glucose, nitrite, ketones, protein and other parameters (Siemens). It was also determined that low concentration of chelator can inhibit acid production by the cariogenic pathogen S. muians in the presence of base, which significantly increases as increasing base concentrations are present (data not shown). It was also discovered that compositions of chelator and base can disrupt the ability of S. mutans to maintain homeostatic pH function, as the optimal pH for S. muians growth and biofilm formation was determined to be pH 6.5, which is also near the average pH of human saliva. For example, at pH input 6.5. the endpoint pH was observed to be 8.5; at pH input 8, the endpoint pH was observed to be 8.5 (data not shown).

Furthermore, it was determined that low concentrations of base may alter the endpoint pH of S. mutans cultures. Screens of base components to use in compositions comprising chelator were performed. Examples of base components screened are presented in Table 2 and FIG. 3 , Briefly, the pH of S. mutans cultures were measured 24 and 48 hr post administration of chelator and candidate base components. Combinations of chelator, base and enhancer agents were also evaluated for affecting metabolic activity and/or metabolism of S. mutans (FIG. 3 ). It was also determined that low concentrations of base (1x) in the presence of low concentrations of chelator (1x) were superior to higher concentrations (2x) of base or chelator alone (data not shown). Synergistic effects on microbial acid production were observed. These data teach that chelator and base may be administered to biologic and inanimate surfaces to limit acid production of the microbes inhabiting them.

Example 4. Compositions and Formulations to Promote Oral Health

Compositions comprising chelator and base can promote oral health. Many microbial metabolic products have beneficial effects for mammals (examples are fermented foods and beverages). Many other microbial metabolic products have pathogenic effects on mammals (Ramsey et al. (2011) PLOS Pathogens). It was observed that S. mutans-specific dextran production was enhanced in the presence of chelator at pH 5.5 to 6.5 (data not shown). It is also observed that S. mutans-specific dextran production can be inhibited when a chelator is administered with a base (FIG. 2 ). It is also observed that the administration of compositions comprising chelator and base can affect microbial metabolism, namely acid production (FIG. 3 ). Synergistic blockade of microbial dextran production and acid production may be important for the prevention of oral pathology such as gingivitis, gum erosion, enamel loss, cavities, periodontitis, mucosal inflammation and others.

In some examples, chelator and base compositions can be formulated in a liquid or solid form and can be administered to mammals to inhibit microbial effectors such as acid, biofilm production, overgrowth and related inflammation. An example of results obtained from oral administration of liquid composition (from about 1 to 3 mL) comprising water, chelator (gamma-cyclodextrin, 10 µg/mL), base (sodium hydroxide, 10 ng/mL) and flavoring agent (cinnamon extract) to human volunteers is presented in FIG. 4A. Subjects were sampled at intervals over about a 12-hour period for salivary pH, protein content and glucose concentration. Subject salivary samples were measured prior to administration and at 30 mins following administration. The liquid composition was ingested in this example as the composition is non-toxic and meant for consumption. Testing was performed using test strips (Multistix, Siemens). Differences in pH, protein content and glucose levels were observed in all subjects.

An example of results obtained from oral administration of rapid melt tablet compositions (ranging from about 320 to about 350 mgs per tablet) comprising filler (in some non-limiting examples, xylitol, sorbitol, Stevia or mannitol was used, ranging from about 310 to about 345 mgs per tablet), chelator (alpha-cyclodextrin, ranging from about 5 to about 30 µg per table), base (pyridoxal-5-phosphate, ranging from about 0.5 to about 15 µg per tablet), enhancer (sodium bicarbonate, ranging from about 0.3 to about 12 µg per tablet), and flavoring agent (peppermint) to human subjects is presented in FIG. 4B. Subject salivary samples were assessed for pH using pH test strip prior to tablet administration and at 30 mins following tablet administration. Differences in pH were observed in all subjects. These data teach that formulations comprising chelator and base compositions can be administered to affect microbial metabolism, reduce pathology-inducing effects and promote oral health.

Example 5. Compositions to Selectively Affect Pathogens Over Commensals

Compositions comprising chelator and base can selectively affect pathogens over commensal microbes of a mammal’s microbiota. The adult human gut contains up to 100 trillion microbial organisms and all mucosal and dermal surfaces of mammals comprise microbes, known as the microbiota of a mammalian host. Specific strains of bacteria have been implicated in the disease pathogenesis of cancer, oral diseases, cardiovascular diseases, diseases of the central nervous system, metabolic diseases and systemic diseases. Streptococcus, Bacteriodes. Clostridia, and Helicobacter species are a few of many microbes having been implicated in disease. Conversely, some microbes, including Lactobacillus acidophilus and Bifidobacterium longum, have been shown to be protective against certain diseases. Thus, the balance between “detrimental” microbes (referred to herein as pathogens) and “beneficial” microbes (referred to herein as commensals) may have implications for disease risk, progression and/or severity in mammals. Non-limiting examples of select chelator and base agents that can be used in compositions to selectively affect pathogens without adversely affecting commensals are presented in FIG. 5 .

Example 6. Health-promoting Compositions And Formulations

Compositions comprising chelator and base can be administered for promoting and maintaining health. Compositions may be formulated in a solid dosing form such as tablet, capsule, powder, crystalline, gum, thin strip, lozenge, patch, or other. Solid dosing formulations may comprise plasticizer, polymer, filling agent, sweetening agent, coloring agent or flavoring agent. Compositions may be formulated in time-release dosing forms.

Solid dosing formulations may be administered frequently or on an as needed basis and may be packaged in a single dose, a multi-dose pack, or other. Formulations may be administered orally for sublingual absorption or may be ingested for absorption in the stomach or intestine. Formulations may also be administered dermally in a patch for absorption by the skin.

Compositions may also be formulated in a liquid dosing form such as liquid, solution, suspension, emulsion, gel, crème, lotion, serum, elixir, or other. Liquid dosing formulations may comprise plasticizer, polymer, filler, sweetening agent, coloring agent, flavoring agent, fragrance, inhalant, evaporant or other. Compositions may be formulated in time-release dosing forms and may comprise nanoparticles, microparticles, or crystals.

Liquid dosing formulations may be administered frequently or on an as needed basis and may be packaged in a single dose, multi-dose pack, concentrate or other. Formulations may be administered: for oral absorption in the mouth or gut; absorption by the skin; aerosolized or nebulized for absorption by the nasal and sinus cavities or by the lungs; rectally for absorption by the gut; for absorption by the eye; in the genitourinary tract; or for absorption by the ear.

Example 7. Administration of Compositions Following Consumption of Sugar- and Acid-Containing Foods And Beverages

Compositions comprising chelator and base can be administered orally for promoting and maintaining health following consumption of foods and beverages that promote microbial growth, undesirable microbial metabolism, or inflammation. Compositions may be formulated in a direct dose or may be formulated in a time-release formula. Compositions may be formulated in liquid or solid dose forms for sublingual absorption or absorption by the stomach or intestine. Compositions may be administered on an as needed basis following consumption of food or beverage.

Example 8. Compositions for Topical Administration

Compositions comprising chelator and base can be used for topical administration to affect microbial biofilm, microbe-specific metabolism and inflammation of the skin. Human skin is a complex organ that protects and regulates the interaction with the external environment. Microbial biofilms permanently inhabit the epidermis with transient microbes that occur through contact-mediated transmission. The topical microbial flora is composed primarily of Gram-positive bacteria and fungus. Topical infections often result from injury to the skin, which provides access of microbial biofilms to the underlying tissue. Large bacterial populations in wounds have been correlated with delayed healing, and control of microbial infection is recognized as an important aspect of wound care (Seth et al. (2012) PLoS One 7:e42897).

Skin-residing microbial biofilms have also been strongly associated with acne and dandruff. Propionibacterium acnes and Staphylococcus epidermidis, in addition to approximately 16 other bacterial species constitute the follicular microbiome (Bek-Thomsen et al. (2008) J Clin Microbiol. 46:3355-3360). Over 85% of the population has been afflicted by this disease, which accounts for more than 14 million acne-related clinical visits per year in the United States. Data also suggest that acne may contribute to significant psychological distress, depression and even increased risk of suicide in teenagers suffering from severe acne (Mancini AJ. (2008) Johns Hopkins Adv Stud in Med. 8: 100-105; Hanisah et al. (2009) J Prim Healthcare. 1:20-25).

An example of a composition to limit the fungal burden residing on the human scalp is presented in FIG. 7 . As exemplified in FIG. 7 , fungus was sampled from human scalps using sterile swabs and cultured in Sabouraud liquid media (pH 5.4). Sensitivity to various compositions were tested using traditional microbiological culture methods (for example, Sabouraud-brain-heart infusion plates supplemented with chloramphenicol to inhibit bacterial growth). Compositionsmay be selected for one or more particular fungal species in a personalized manner. In other non-limiting examples, subjects were treated for 5 mins with control solution (10 mM NaCl) or various compositions (50 µL, per donor) on the left wrist. Treatment zones were outlined on each subject by permanent marker prior to washing with sterile water. Treatment zones were then sampled by sterile swab and compared to sampling the untreated wrist (right wrist). Swabs were plated on Sabouraud-brain-heart infusion plates supplemented with chloramphenicol to inhibit bacterial growth and allowed to grow for 5 days. Fungal growth between treatment and control zones were assessed and tabulated. Results from these studies may be used to inform selection of a composition with desired effectiveness. Compositions may be formulated with detergents, surfactants, natural oils, coloring agents, fragrances, polymers, salts, waxes, emulsifiers, antioxidants, and moisturizers.

Compositions for topical administration may be formulated in washes, wipes, make-up, crèmes, lotions, shampoos, conditioners, gels, mousse, sprays, deodorants or other.

Compositions may be applied to skin surfaces, followed by manual rubbing and massaging actions. Compositions may also be contacted to skin surfaces by spray, followed by manual rubbing and massaging actions. Yet in other methods, compositions may be applied to the skin, followed by removal of the compositions by rinsing. Topical compositions may be applied routinely in a single dose format or may be applied periodically throughout the day.

In some non-limiting examples, topical compositions may be used to reduce microbial burdens, to reduce microbial metabolic activity, to reduce metabolically-derived malodor on skin surfaces, and to reduce microbe-triggered inflammation of the skin.

Example 9. Composition for Affecting Malodor

Malodor is considered an aesthetic problem by many people worldwide. Considerable time and money is spent to limit odor due to inherent social and cultural biases. Current methods to affect malodor involve the application of “odor masking” technologies, such as deodorant and perfume. Other methods involve the application of “odor sequestration” technologies such as tales and powders. Yet other methods involve the application of “antiperspirant” creams, pastes, solutions and others to block sweat and oil secretion by the skin.

Here, we present compositions affecting microbe-mediated malodor. Mucosal and dermal malodor is known to arise from the metabolic activity microbes living on the skin and mucosal surfaces of a mammal. Malodor is produced by aromatic metabolic waste products generated from microbial metabolism. Commonly, commensal microbes use the secreted oils of the skin as carbon sources for energy production and use consumed food as carbon sources in the gut of the mammalian host. Aromatic waste products may include butyric acid, acetic acid, propionic acid, sulfites, volatile aromatic compounds and other. Chelator and base compositions may be formulated in a powder, crème, gel, solid, lotion, wash, gum, lozenge, tablet, capsule, liquid, gel, deodorant or wipe to inhibit microbe-mediated odor production. Compositions may be administered topically, orally, or rectally by manual application, through the use of a device such as a wipe. Compositions may be administered frequency on a daily basis or on an as needed basis.

Example 10. Health-Promoting Compositions for Surfaces

Compositions comprising chelator and base can be administered to food and surfaces to promote health. Pathogen-harboring microbial biofilm contamination of food is a significant problem worldwide. Foodborne illness is not decreasing in occurrence despite improvements in food handling, food processing and food storage practices. Foodborne illness accounts for 48 million illnesses, 128,000 hospitalizations and 3,000 deaths each year in the United States (USDA). Every year in the US, millions of tons of chicken, beef and pork products are recalled due to potential food safety issues (CDC).

Compositions comprising chelator and base may be used for food safety. In some embodiments, compositions may be administered to the surface of foods to reduce the microbial CFU burden (examples are demonstrated in FIG. 8 ). In these embodiments, compositions or commercial vegetable wash was administered to fruits and vegetables for about 5 to 15 seconds and rinsed with tap water. Microbial CFU burden was evaluated using standard microbiologic techniques. Various chelator and base combinations were superior to commercial products and provide a safe, nontoxic and consumable method for promoting health.

Some compositions may be used as an additive in processed food and beverage and can be formulated in powders, liquids, gels, concentrates or other. Preferred methods of food safety compositions relate to the contacting of food and beverage during the course of preparation, processing and/or packaging said food and beverage.

Said food safety compositions may also be used as device surface treatments in food and beverage processing and preparation. Methods using food safety compositions relate to the administration of said composition to device surfaces that contact food during the course of processing and preparation. Methods may include the spraying of said composition to cutting blocks, conveyor belts, knives, forks, skewers, processing tools, processing machinery, packaging machinery and packaging materials.

Hospital-acquired (nosocomial) infections from contaminated devices or pathogen-carrying healthcare professionals results in incidental infections at a rate of approximately 4-5.5% in in-patient populations annually. The healthcare costs associated with biofilm contamination are estimated at $4.5 billion USD (Emori and Gaynes (1993) Clin Microbiol. Rev. 6:428-442). Numerous approaches have been employed to reduce unnecessary exposure to pathogen-harboring biofilms, however, there remains an urgent need for novel and cost-effective approaches to prevent biofilm-associated illness through the administration of anti-microbial sprays, washes and additives.

Compositions comprising chelator and base may be used on biologic and inanimate surfaces as general cleaners to promote health. Exemplary surfaces may include doorknobs, keyboards, remote controls, cell phones, handles, elevator buttons, floors, counters, faucets, tools and others. Compositions for administration to surfaces may be formulated as powders, gels, foams and liquids. Methods of administering compositions relate to the contacting of surfaces with the composition for a desirable period of time to disinfect, cleanse, or treat contaminated surfaces.

Example 11. Method of Testing Followed by the Selection of Desirable Health-Promoting Chelator and Base Composition

Test methods to measure indicators of microbe-mediated inflammation, unwanted microbial metabolism, biofilm, or microbial overgrowth in a mammal may relate to the use of one or more test to measure the pH, nitrate level, protein content, leukocyte esterase level, cytokine level, dextran content of a sample or a surface. Test may be utilized on a routine basis, daily, weekly, monthly or on an as needed basis. The use test may aid in the: selection of health-promoting composition, determination of dose, dose form, formulation, frequency of use, route of administration and effectiveness.

Test methods may include the administration of a dye to stain surfaces or samples suspected of having evidence of microbe-mediated inflammation, unwanted microbial metabolism, biofilm, or microbial overgrowth. Dye stains may comprise commercial formulations including but not limited to dextran-binding dyes, hematoxylin and eosin, immunohistochemical stains, nitrite- or nitrate-sensitive dyes, protein dyes, sulfur-sensitive dyes and other. Test methods may also include the use of a test strip, lateral flow test, standard sandwich immunoassay, flow cytometric or other methods.

The examples, which are intended to be purely exemplary of the invention and should therefore not be considered to limit the invention in any way, also describe and detail aspects and embodiments of the invention discussed above. The foregoing examples and detailed description are offered by way of illustration and not by way of limitation. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. 

1. A composition comprising a chelator and a base, wherein the chelator and base provide microbial affecting activity.
 2. The composition of claim 1, wherein the chelator is selected from the group consisting of siderophores, natural chelators and synthetic chelators.
 3. The chelator of claim 1, wherein the chelator is cyclodextrin or cyclodextrin derivative, ferrichrome, citrate, EDTA, EGTA, pectin or modified pectin.
 4. The composition of claim 1, wherein more than one chelator is used.
 5. The composition of claim 1, wherein the concentration of chelator is between 0.0005% and 30% of the composition.
 6. The composition of claim 1, wherein the base is selected from the group consisting of natural bases, synthetic bases and agents having basic properties.
 7. The composition of claim 6, wherein the base is KOH, NaOH, pyridoxal-5-phosphate, pyridoxamine, pyridoxine. vitamin K, lysine, arginine, lysozyme, alpha-galactase, tris amine or sodium bicarbonate.
 8. The composition of claim 1, wherein more than one base is used.
 9. The composition of claim 1, wherein the concentration of base is between 0.0001% and 15% of the composition.
 10. The composition of claim 1, further comprising an enhancer.
 11. The composition of claim 1, wherein the enhancer is proline, phenylalanine, boric acid, ascorbic acid and extracts from citrus, berries, teas, peppermint, mint or cinnamon and the concentration is between 0.0001% and 10% of the composition.
 12. The composition of claim 1, wherein the composition is for oral care.
 13. The composition of claim 1, wherein the base comprises sodium bicarbonate and pyridoxal-5-phosphate and the chelator comprises alpha-cyclodextrin.
 14. The composition of claim 1, wherein the composition is formulated in a tablet, capsule, rapid melt tablet, thin strip, gum or mouthwash.
 15. The composition of claim 1, wherein the composition is formulated for administration at least once per day.
 16. The composition of claim 1, wherein the composition is used to promote oral health, treat or prevent cavities, periodontitis, halitosis and gingivitis.
 17. The composition of claim 1, wherein the composition is for use following consumption of a phosphoric acid or ascorbic acid containing beverage.
 18. The composition of claim 1, wherein the composition is for use following consumption of food.
 19. A method of promoting oral health in a mammal comprising: (i) identifying an individual at increased risk for developing or exhibiting signs of oral disease; (ii) measuring pH, leukocyte esterase, nitrate, microbial marker levels, or plaque-staining dye retention in the mouth of the individual; (iii) comparing said levels to healthy levels to determine if oral pathology is present; and (iv) contacting an effective amount of a composition comprising a chelator and a base to the oral surface if evidence of oral pathology is present.
 20. The method of claim 19, wherein said method is repeated on a daily, a monthly, quarterly or annual basis.
 21. The method of claim 19, wherein the composition comprises EDTA or alpha-cyclodextrin and sodium bicarbonate or pyridoxal-5-phosphate.
 22. The method of claim 21, wherein the EDTA and alpha-cyclodextrin comprises between 0.0001% and 30% of the composition.
 23. The method of claim 21, wherein the effective amount of sodium bicarbonate and pyridoxa1-5-phosphate is between 0.0001% and 15% of the composition.
 24. The method of claim 19, wherein oral pathology is indicated by the individual having an oral pH below 6.2.
 25. The method of claim 19, wherein the individual is determined to have oral pathology based on the presence of one or more of halitosis, tooth plaque, tooth decay, or a cavity.
 26. The method of claim 19, wherein the individual is determined to have oral pathology based on the presence of Streptococcus mutans. 